Submissions for variant NM_177438.3(DICER1):c.4616C>T (p.Thr1539Met)

gnomAD frequency: 0.00013  dbSNP: rs747901058

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232937	SCV000291689	likely benign	DICER1-related tumor predisposition	2024-12-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000494503	SCV000581549	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-19	criteria provided, single submitter	clinical testing	The p.T1539M variant (also known as c.4616C>T), located in coding exon 22 of the DICER1 gene, results from a C to T substitution at nucleotide position 4616. The threonine at codon 1539 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in four individuals from one family who were all affected with DICER1-related tumors; however, these individuals were also found to carry a truncating DICER1 mutation in addition to this alteration (Kuhlen M et al. Eur. J. Pediatr. 2016 Apr;175:593-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV001201135	SCV001372177	likely benign	not specified	2019-07-01	criteria provided, single submitter	curation	ACMG criteria met: BP1, BP2, PB4
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003128604	SCV002011554	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV003128604	SCV003805494	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed with a truncating DICER1 variant (phase unknown) in four individuals from a single family, each with DICER1-related tumors (Kuhlen et al., 2015); This variant is associated with the following publications: (PMID: 29708584, 29762508, 28748527, 35384518, 26526666)
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004776281	SCV005382087	uncertain significance	Pediatric high-grade glioma		criteria provided, single submitter	research